title: Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice.
abstract: BACKGROUND
  Inflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.
  
  
  METHODS
  The inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.
  
  
  RESULTS
  The ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.
  
  
  CONCLUSIONS
  Here we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.
authors.affiliation: Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, University of Edinburgh, General Western Hospital, Edinburgh, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Coste
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Greig
authors.affiliation: Galapagos SASU, Romainville, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mollat
authors.affiliation: Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, University of Edinburgh, General Western Hospital, Edinburgh, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Rose
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Mohini
authors.initials: M
authors.lastname: Gray
authors.affiliation: Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, University of Edinburgh, General Western Hospital, Edinburgh, UK.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.affiliation: Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, University of Edinburgh, General Western Hospital, Edinburgh, UK.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: van 't Hof
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism*; D006588:Hexanones / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053245:RANK Ligand / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
chemical_list: C556521:ABD 328; C000595267:ABD345; D001713:Biphenyl Compounds; D006588:Hexanones; D016328:NF-kappa B; D053245:RANK Ligand; D048069:Tumor Necrosis Factors
keywords: Osteoporosis; Rheumatoid Arthritis; TNF-alpha